Opioid receptor active compounds

ABSTRACT

The invention provides compounds of formula I: 
                         
wherein R 1  to R 4  and n have any of the meanings defined in the specification and their pharmaceutically acceptable salts. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I, and therapeutic methods for treating pain and treating other conditions which involve, for example, binding opioid receptors using compounds of formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/354,990, filed Feb. 7, 2002, entitled “OPIOID RECEPTORACTIVE COMPOUNDS.”

BACKGROUND OF THE INVENTION

Among the three classes of opioid receptors, designated delta (δ), kappa(κ), and mu (μ), recent evidence suggests that δ-selective opioids couldbe potentially useful as analgesics devoid of the numerous side effects(e.g., respiratory depression, physical dependence and gastrointestinaleffects) associated with narcotics such as morphine (E. J. Bilsky etal., J. Pharmacol. Exp. Ther., 273, 359 (1995)). Moreover, selectiveantagonists of δ receptors have been shown to modulate the developmentof tolerance and dependence to μ agonists such as morphine (E. E.Abdelhamid et al., J. Pharmacol. Exp. Ther., 258, 299 (1991)), tomodulate the behavioral effects of drugs of abuse such as cocaine (L. D.Reid et al., Life Sci., 52, PL67 (1993)), and to elicit favorableimmunomodulatory effects (R. V. House et al., Neurosci. Lett., 198, 119(1995)). The δ-selective opioids thus represent extremely attractivecandidates for a broad range of novel pharmaceutical applicationsincluding powerful yet safe analgesics, immunomodulatory agents fortreating immune disorders, and new treatments for drug addiction. Opioidnarcotics can be potent painkillers, but they are also addictive. Thedelta (δ) receptors, along with the related kappa (κ) and mu (μ)receptors, are found on cells located throughout the central andperipheral nervous system. The receptors normally bind with opioidpeptides (e.g., enkephalins) that the body produces. By binding to thereceptors, these peptides modulate endocrine, cardiovascularrespiratory, gastrointestinal, and immune functions. Opioid narcoticsare alkaloids, with molecular structures quite distinct from opioidpeptides. However, the narcotic drugs and opioid peptides share commonstructural features (known as pharmacophores) that enable the drugs tobind to the opioid receptors. When they bind to these receptors, thenarcotics exert various effects on the perception of pain,consciousness, motor control, mood, and autonomic function. They alsoinduce physical dependence. However, recently published studiesdemonstrate that compounds, or combinations of compounds, that act inconcert as selective μ agonists and δ antagonists (mixed μ/δ agonists)exhibit the potency of opioid pain killers without their negative sideeffects, such as physical addiction, physical dependence, narcoticaddiction, and like conditions. See P. W. Schiller et al., J. Med.Chem., 1999, 42, 3520.

Despite these reports there remains a need for non-opioid compoundswhich possess high binding affinity and high selectivity for opioidreceptors. Such compounds would be useful for treating pain as well asother opioid related conditions.

SUMMARY OF THE INVENTION

Certain triazole compounds, such as di-substituted triazole ringcompounds and tri-substituted triazole ring compounds, have beendiscovered that exhibit high binding affinity and high selectivity foropioid receptors. Moreover, these compounds exhibit excellentbioavailability. These “non-opioid” compounds are structurally distinctfrom known opioid compounds such as naltrindole (NTI) andspiroindanyloxymorphone (SIOM).

Accordingly, the invention provides a compound of formula I:

wherein:

R₁ is aryl, Het, (C₁₋₇)alkyl, or (C₃₋₁₂)cycloalkyl, which (C₁₋₇)alkyl or(C₃₋₁₂)cycloalkyl are each independently optionally substituted withfrom 1 to 5 aryl, Het, OR_(a), halo, NO₂, NR_(a)R_(b), cyano,CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b), orP(═O)(OR_(a))(R_(a));

R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, aryl, Het, or a group thatincludes one or more (1, 2, 3, or 4) basic atoms (e.g. atoms that candonate electrons or accept a proton, such as N, O, S, or P atoms);

R₃ is H, or (C₁₋₇)alkyl;

each R₄ is independently OR_(a), trifluoromethoxy, trifluoromethyl,halo, NO₂, NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl;

-   -   R_(a) and R_(b) are each independently H, (C₁₋₇)alkyl,        (C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl,        or R_(a) and R_(b) together with a nitrogen to which they are        attached form a Het;

wherein any aryl or Het of R¹ or R² is optionally substituted with from1 to 4 substituents independently selected from OR_(a),trifluoromethoxy, trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano,CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b),P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or(C₃₋₁₂)cycloalkyl;

m is 0, 1, or 2; and

n is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention also provides:

a pharmaceutical composition comprising a compound of the invention anda pharmaceutically acceptable excipient (the composition preferablycomprises a therapeutically effective amount of the compound or salt);

a method for treating a disease or condition in a mammal (e.g. a human)wherein an opioid receptor is implicated and modulation of receptorfunction is desired comprising administering an effective modulatoryamount of a compound of the invention;

a method for treating or preventing a disease or opioid receptor relatedcondition (e.g. pain) in a mammal comprising administering atherapeutically effective amount of a compound of the invention;

a compound of the invention for use in medical diagnosis or therapy(e.g. the treatment or prevention of opioid receptor related disease orcondition such as pain, anxiety, obesity, depression, or a stressrelated disease);

the use of a compound of the invention to prepare a medicament usefulfor treating or preventing a disease or opioid receptor relatedcondition (e.g. the treatment or prevention of opioid receptor relateddisease or condition such as pain, anxiety, obesity, depression, or astress related disease);

a method of treating pain, comprising administering to a mammal in needof such treatment, an effective amount of a compound of the invention;

a method for modulating opioid receptor function in vitro or in vivo,comprising administering an effective modulatory amount of a compound ofthe invention; and

a method for modulating opioid receptor function in vitro or in vivo,comprising contacting an opioid receptor with an effective modulatoryamount of a compound of the invention.

The invention also provides novel intermediates (e.g. compounds offormula III and IV) and processes disclosed herein that are useful forpreparing compounds of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-C illustrate representative dose-response curves fromcompetitive binding assays and compounds of the present invention forthe delta (δ), mu (μ), and kappa (κ) receptors, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straightand branched groups; but reference to an individual radical such as“propyl” embraces only the straight chain radical, a branched chainisomer such as “isopropyl” being specifically referred to.

“Aryl” denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to twenty ring atoms in which at least onering is aromatic.

“Het” is a four- (4), five- (5), six- (6), or seven- (7) memberedsaturated or unsaturated heterocyclic ring having 1, 2, 3, or 4heteroatoms selected from the group consisting of oxy, thio, sulfinyl,sulfonyl, and nitrogen, which ring is optionally fused to a benzenering. Het includes “heteroaryl,” which encompasses a radical attachedvia a ring carbon of a monocyclic aromatic ring containing five or sixring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms eachselected from the group consisting of non-peroxide oxy, thio, and N(X)wherein X is absent or is H, O, C₁₋₄alkyl, phenyl or benzyl, as well asa radical of an ortho-fused bicyclic heterocycle of about eight to tenring atoms derived therefrom, particularly a benz-derivative or onederived by fusing a propylene, trimethylene, or tetramethylene diradicalthereto.

“Treat” or “treatment” or “treating” mean to lessen, eliminate, inhibit,improve, alter, or prevent a disease or condition, for example byadministration of compound of the present invention.

“Pain” refers to, for example, a localized or generalized physicalsuffering associated with bodily disorder, such as a disease or aninjury, and can include a basic bodily sensation induced by a noxiousstimulus, received by naked nerve endings, characterized by physicaldiscomfort such as pricking, throbbing, or aching, and typically leadsto evasive action. A specific example is neuropathic pain which is achronic condition associated with diabetes, chronic inflammation,cancer, and herpes virus infection.

“Analgesia” or “pain relief” includes, for example, inducing orproviding insensitivity to pain, and preferably without loss ofconsciousness.

“Diseases or conditions where an opioid receptors are implicated” and“opioid receptor related disease or conditions” include, inflammation(e.g. inflammation in such diseases as vascular diseases, migraineheadaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin'sdisease, sclerodoma, rheumatic fever, type I diabetes, myastheniagravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet'ssyndrome, polymyositis, gingivitis, hypersensitivity, swelling occurringafter injury, myocardial ischemia, allergic rhinitis, respiratorydistress syndrome, endotoxin shock syndrome, atherosclerosis), pain,headache, fever, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus, and juvenile arthritis), asthma, bronchitis, menstrualcramps, tendinitis, bursitis, skin related conditions (e.g. psoriasis,eczema, burns and dermatitis), gastrointestinal conditions (e.g.inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, and ulcerative colitis), cancer (e.g. colorectal cancer),ophthalmic diseases (e.g. retinitis, retinopathies, conjunctivitis,uveitis, ocular photophobia, and acute injury to the eye tissue),pulmonary inflammation (such as that associated with viral infectionsand cystic fibrosis), central nervous system disorders (such as corticaldementias including Alzheimer's disease), and central nervous systemdamage (e.g. resulting from stroke, ischemia, or trauma). Compounds ofthe invention may also be useful for modifying the effects of otherbiologically active compounds (for example for treating narcoticaddiction), and for treating diseases or conditions other than onesassociated with receptors, for example, blocking, inhibiting, orpromoting, metabolic pathways or enzyme function, and selectivelyinteracting with genetic material.

In one embodiment R₂ is a group that includes one or more (1, 2, 3, or4) basic atoms (e.g. atoms that can donate electrons or accept a proton,such as N, O, S, or P atoms). It is believed that a basic atom in thisgroup mimics the basic nitrogen atom found in classical morphine-likeopioids. If so, the basic atom can become protonated by acceptance of aproton, thus enhancing opioid binding affinity. Accordingly, for acompound of formula I, it may be preferred to have a group R₂ having abasic group that is spatially oriented so that it can mimic the basicnitrogen atom found in classical morphine-like opioids. In oneembodiment, the group has a total of about 20 or less atoms includingcarbon atoms and one or more (1, 2, 3, or 4) basic atoms (e.g. N, O, S,or P). In another embodiment, the group has a total of about 10 or lessatoms including carbon atoms and one or more (1, 2, 3, or 4) basic atoms(e.g. N, O, S, or P).

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase). It isalso well known in the art and, for example, as illustrated hereinbelowhow to determine opioid receptor activity, for example, delta, mu, orkappa, or related receptor activity using the standard tests describedherein, or using other similar tests. In particular, it is understoodthat compounds of formula I or II can contain chiral centers, forexample, in any of the R₁–R₉ substituents. It is also understood thatcompounds of the invention, such as formula I or formula II wherein, forexample R₂ is OH or R₃ is hydrogen, can exist in the “enol” form or thecorresponding tautomeric “keto” form, and that all such tautomers areincluded as compounds within the scope of the present invention.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating a lower and upper number of carbonatoms in the moiety, i.e., the prefix C_(i-j) indicates a moiety of theinteger “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, C₁₋₇alkyl refers to alkyl of one to seven carbon atoms,inclusive.

The compounds of the present invention are generally named according tothe IUPAC nomenclature system. Abbreviations which are well known to oneof ordinary skill in the art may be used (e.g. “Ph” for phenyl, “Me” formethyl, “Et” for ethyl, “h” for hour or hours and “rt” for roomtemperature).

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents. The compounds of the invention include compounds offormula I or formula II having any combination of the values, specificvalues, more specific values, and preferred values described herein.

Specifically, aryl can be phenyl, naphthyl, anthracenyl, phenanthrenyl,fluorenyl, tetrahydronaphthyl, or indanyl.

Specifically, C₁₋₇alkyl can be methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, hexyl, or heptyl;(C₃₋₁₂)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, or multi-cyclic substituents of theformulas

C₁₋₇alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy,iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy,or heptyloxy; C(═O)alkyl or (C₂₋₇)alkanoyl can be acetyl, propanoyl,butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl, or heptanoyl; aryl canbe phenyl, indenyl, or naphthyl; Het can be pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, or heteroaryl; and heteroaryl can befuryl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl,isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (orits N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

A specific value for Het is a five- (5), six- (6), or seven- (7)membered saturated or unsaturated ring containing 1, 2, 3, or 4heteroatoms, for example, non-peroxide oxy, thio, sulfinyl, sulfonyl,and nitrogen; as well as a radical of an ortho-fused bicyclicheterocycle of about eight to twelve ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, tetramethylene or another monocyclic Het diradicalthereto.

A specific value for R₁ is aryl.

Another specific value for R₁ is aryl substituted with from 1 to 5substituents.

Another specific value for R₁ is phenyl substituted with from 1 to 5substituents.

Another specific value for R₁ is phenyl substituted with from 1 to 3substituents.

Another specific value for R₁ is phenyl substituted with one n-butyl,iso-butyl, methyl, ethyl, or tert-butyl.

Preferred R₁ groups and substitutents of R₁, such as R₅, R₆, R₇, R₈, orR₉, are sterically bulky, for example, phenyl, naphthyl, pyridyl, andlike aryl and Het groups, and sec-butyl, tert-butyl, cyclohexyl,adamantyl, and like alkyl or cycloalkyl groups.

Another specific value for R₁ is tert-butyl phenyl.

Another specific value for R₁ is 2-tert-butylphenyl, 3-tert-butylphenyl,or 4-tert-butylphenyl.

Another specific value for R₁ is 3-tert-butylphenyl, or4-tert-butylphenyl.

Another specific value for R₁ is phenyl substituted with (C₁₋₇)alkyl and(C₁₋₇)alkoxy.

Another specific value for R₁ is phenyl substituted with tert-butyl andmethoxy.

Another specific value for R₁ is Het.

Another specific value for R₁ is Het substituted with from 1 to 4substituents.

Another specific value for R₁ is pyridyl substituted with from 1 to 4substituents.

Another specific value for R₁ is pyridyl substituted with from 1 to 4(C₁₋₇)alkyl substituents.

Another specific value for R₁ is pyridyl substituted with a (C₁₋₇)alkyl.

Another specific value for R₁ is pyridyl substituted with a tert-butyl.

A specific value for R₂ is H.

Another specific value for R₂ is OR_(a).

Another specific value for R₂ is SR_(a).

Another specific value for R₂ is (C₁₋₇)alkyl.

Another specific value for R₂ is NR_(c)R_(d).

Another specific value for R₂ is N(CH₃)₂.

Another specific value for R₂ is a piperazino, pyrrolidino, piperidino,morpholino, or thiomorpholino ring.

A specific value for R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a),SR_(a), NR_(c)R_(d), aryl, or Het.

Another specific value for R₂ is a group that includes one or more Natoms.

Another specific value for R₂ is a group that has a total of 20 or lessatoms including one or more carbon atoms and one or more basic atoms

Another specific value for R₂ is a group that has a total of 20 or lessatoms including one or more carbon atoms and one or more nitrogen atoms.

Another specific value for R₂ is a group that has a total of 20 or lessatoms including one or more carbon atoms and one or two nitrogen atoms.

Another specific value for R₂ is a group that has a total of 10 or lessatoms including one or more carbon atoms and one or more basic atoms

Another specific value for R₂ is a group that has a total of 10 or lessatoms including one or more carbon atoms and one or more nitrogen atoms.

Another specific value for R₂ is a group that has a total of 10 or lessatoms including one or more carbon atoms and one or two nitrogen atoms.

Another specific value for R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, Het, R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is group that includes one or morebasic atoms; and p is 1–7.

Another specific value for R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, Het, R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is OR_(a), SR_(a), NR_(c)R_(d),piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino; andp is 1–7.

Another specific value for R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, Het, R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is NR_(c)R_(d); and p is 1–7.

Another specific value for R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, Het, R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is piperazino, pyrrolidino,piperidino, morpholino, or thiomorpholino; and p is 1–7.

Another specific value for R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is group that includes one or morebasic atoms; and p is 1–7.

Another specific value for R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is OR_(a), SR_(a), NR_(c)R_(d),piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino; andp is 1–7.

Another specific value for R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is NR_(c)R_(d); and p is 1–7.

Another specific value for R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is piperazino, pyrrolidino,piperidino, morpholino, or thiomorpholino; and p is 1–7.

Another specific value for R₃ is (C₁₋₇)alkyl.

Another specific value for R₃ is methyl.

Another specific value for R₃ is ethyl.

Another specific value for R₃ is tert-butyl.

A specific value for R₅ is tert-butyl.

A specific value for R₅ is OCH₃ and R₈ is tert-butyl.

A specific value for R₆ is tert-butyl.

A specific value for R₇ is tert-butyl.

A specific compound is a compound of formula I wherein:

R₁ is aryl, Het, (C₁₋₇)alkyl, or (C₃₋₁₂)cycloalkyl, which (C₁₋₇)alkyl or(C₃₋₁₂)cycloalkyl are each independently optionally substituted withfrom 1 to 5 aryl, Het, OR_(a), halo, NO₂, NR_(a)R_(b), cyano,CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b), orP(═O)(OR_(a))(R_(a));

R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d),aryl, or Het;

R₃ is H, or (C₁₋₇)alkyl;

R₄ is H, OR_(a), trifluoromethoxy, trifluoromethyl, halo, NO₂,NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl;

R_(a) and R_(b) are each independently H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl, or R_(a)and R_(b) together with a nitrogen to which they are attached form aHet;

R_(c) and R_(d) are each independently H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl;

wherein any aryl or Het of R¹ or R² is optionally substituted with from1 to 4 substituents independently selected from OR_(a),trifluoromethoxy, trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano,CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b),P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or(C₃₋₁₂)cycloalkyl; and

m is 0, 1, or 2;

n is 1;

or a pharmaceutically acceptable salt thereof.

Another specific compound of the invention is a compound of formula II:

wherein:

R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, aryl, Het, or a group thatincludes one or more (1, 2, 3, or 4) basic atoms (e.g. atoms that candonate electrons or accept a proton, such as N, O, S, or P atoms);

R₃ is H, or (C₁₋₇)alkyl;

each R₄ is independently OR_(a), trifluoromethoxy, trifluoromethyl,halo, NO₂, NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl;

R₅, R₆, R₇, R₈, and R₉ are each independently H, OR_(a),trifluoromethoxy, trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano,CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b),P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or(C₃₋₁₂)cycloalkyl;

R_(a) and R_(b) are each independently H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl, or R_(a)and R_(b) together with a nitrogen to which they are attached form aHet;

wherein any aryl or Het of R² is optionally substituted with from 1 to 4substituents independently selected from OR_(a), trifluoromethoxy,trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a),SO_(m)R_(a), S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl,(C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl; and

m is 0, 1, or 2; and

n is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

A specific compound of formula II is a compound wherein R₂ is H,(C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, orHet; R_(c) and R_(d) are each independently H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl; and n is0 or 1.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ is(C₁₋₇)alkyl.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ is(C₁₋₇)alkoxy.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ isOCH₃.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ istert-butyl.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ isOH.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, and R₉is H.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ ishalo.

Another specific compound is a compound wherein R₅, R₆, R₇, R₈, or R₉ isNO₂, (C₂₋₇)alkanoyloxy, (C₃₋₁₂)cycloalkyl, Het, or aryl.

Another specific compound is a compound wherein R₅ is OH and R₈ istert-butyl.

Another specific compound is a compound wherein R₅ or R₆ is OCH₃, andR₇, R₈, or R₉ is tert-butyl.

Another specific compound is a compound wherein R₅ or R₆ is OH, and R₇,R₈, or R₉ is tert-butyl.

A specific compound is1-{3-[4-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene; or apharmaceutically acceptable salt thereof.

Another specific compound is1-{3-[4-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol; or apharmaceutically acceptable salt thereof.

Another specific compound is1-{3-[5-(tert-butyl)-2-methoxyphenyl](1,2,4-triazol-4-yl)}-3-methoxybenzene;or a pharmaceutically acceptable salt thereof.

Another specific compound is1-{3-[5-(tert-butyl)-2-hydroxyphenyl]-(1,2,4-triazol-4-yl)}-3-phenol; ora pharmaceutically acceptable salt thereof.

Another specific compound is1-{3-[3-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene; or apharmaceutically acceptable salt thereof.

Another specific compound is1-{3-[3-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol; or apharmaceutically acceptable salt thereof.

Compounds of the invention can be prepared as illustrated in the schemesbelow, by procedures analogous thereto, or by procedures which are knownto one of ordinary skill in the art. All of the variables used in theschemes are as defined below or elsewhere herein. Scheme 1 illustratesthe preparation of representative compounds of the invention, compounds4 and 5.

Scheme 2 illustrates the preparation of an intermediate compound 6a thatis useful for preparing compounds of formula I.

Scheme 3 illustrates a reaction scheme for the preparation of anintermediate compound 6b that is useful for preparing compounds offormula I.

The invention also provides a method for preparing a compound of formulaI:

wherein R₁–R₄ and n have the values, specific values, or preferredvalues described herein comprising: reacting a corresponding compound offormula III:

with a formate source to provide the compound of formula I. The reactioncan be carried out under any suitable conditions. For example, thereaction can conveniently be carried out by heating the compound offormula III with pentylformate.

The invention also provides a method for preparing a compound of formulaII:

wherein R²–R⁹ have the values, specific values, or preferred valuesdescribed herein comprising: reacting a corresponding compound offormula IV:

with a formate source to provide the compound of formula II. Thereaction can be carried out under any suitable conditions. For example,the reaction can conveniently be carried out by heating the compound offormula III with pentylformate.

Other conditions suitable for formation of the di- or tri-substitutedring systems from a variety of intermediates as illustrated herein arewell known to the art. For example, see Feiser and Feiser, “Reagents forOrganic Synthesis”, Vol. 1, 1967; March, J. “Advanced OrganicChemistry”, John Wiley & Sons, 4^(th) ed.1992; House, H. O., “ModernSynthetic Reactions”, 2^(nd) ed., W. A. Benjamin, New York, 1972; andLarock, R. C., Comprehensive Organic Transformations, 2^(nd) ed., 1999,Wiley-VCH Publishers, New York.

The starting materials employed in the synthetic methods describedherein are commercially available, have been reported in the scientificliterature, or can be prepared from readily available starting materialsusing procedures known in the field. It may be desirable to optionallyuse a protecting group during all or portions of the above describedsynthetic procedures. Such protecting groups and methods for theirintroduction and removal are well known in the art. See Greene, T. W.;Wutz, P. G. M. “Protecting Groups In Organic Synthesis” 2^(nd) ed.,1991, New York, John Wiley & Sons, Inc. The invention also provides amethod for preparing a compound of formula I comprising deprotecting acorresponding compound comprising one or more protecting groups (e.g.one or more hydroxy or amino protecting groups). For example, theinvention provides a method for preparing a compound of formula Iwherein R₃ is hydrogen comprising deprotecting a corresponding compoundwherein R₃ is hydroxy protecting group (e.g. methyl).

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, hydrobromide, sulfate, nitrate,bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example, by reacting asufficiently basic compound such as an amine with a suitable acidaffording a physiologically acceptable anion. Alkali metals, forexample, sodium, potassium or lithium, or alkaline earth metal salts,for example calcium, of carboxylic acids can also be made.

Compounds of the present invention can conveniently be administered in apharmaceutical composition containing the compound in combination with asuitable excipient, the composition being useful in combating viralinfections. Pharmaceutical compositions containing a compoundappropriate for antiviral use are prepared by methods and containexcipients which are well known in the art. A generally recognizedcompendium of such methods and ingredients is Remington's PharmaceuticalSciences by E. W. Martin (Mark Publ. Co., 15^(th) Ed., 1975). Thecompounds and compositions of the present invention can be administeredparenterally, for example, by intravenous, intraperitoneal orintramuscular injection, topically, orally, or rectally, depending onwhether the preparation is used to treat internal or external viralinfections.

For oral therapeutic administration, the active compound may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations typically contain atleast about 0.1% of active compound. The percentage of the compositionsand preparations may, of course, be varied and may conveniently bebetween about 2 to about 60% of the weight of a given unit dosage form.The amount of active compound in such therapeutically usefulcompositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The compounds or compositions can also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers. Thickeners such as synthetic polymers,fatty acids, fatty acid salts and esters, fatty alcohols, modifiedcelluloses or modified mineral materials can also be employed withliquid carriers to form spreadable pastes, gels, ointments, soaps, andthe like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of the invention can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The compound is conveniently administered in unit dosage form; forexample, containing 5 to 1,000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

For internal infections, the compositions can be administered orally orparenterally at dose levels, calculated as the free base, of about 0.1to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and canbe used in man in a unit dosage form, administered one to four timesdaily in the amount of 1 to 1,000 mg per unit dose.

For parenteral administration or for administration as drops, as for eyetreatments, the compounds are presented in aqueous solution in aconcentration of from about 0.1 to about 10%, more preferably about 0.1to about 7%. The solution may contain other ingredients, such asemulsifiers, antioxidants or buffers.

Generally, the concentration of the compound(s) of formula I in a liquidcomposition, such as a lotion, will be from about 0.1–25, preferablyfrom about 0.5–10, weight percent. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1–5 weightpercent, preferably about 0.5–2.5 weight percent.

The exact regimen for administration of the compounds and compositionsdisclosed herein will necessarily be dependent upon the needs of theindividual subject being treated, the type of treatment and, of course,the judgment of the attending practitioner.

The binding activity and binding selectivity of the compounds of thepresent invention are excellent predictors of the analgesic activity ofcompounds of the invention. The binding activity and binding selectivitycan be determined using pharmacological models which are well known tothe art, or using the assays described below. Exemplary results ofbiological testing are summarized in Table 2 below.

The non-opioid compounds of the present invention can have improvedbioavailability compared with, for example, naltrindole (NTI) andspiroindanyloxymorphone (SIOM). The bioavailability of a pharmaceuticalcompound relates to the rate and extent at which the active ingredientreaches systemic circulation. To estimate the bioavailability of eachcompound, there was calculated the so-called log P that provides ameasure of the molecule's hydrophobic-hydrophilic balance. Values of logP for most pharmaceuticals vary from −5 (very hydrophilic) to +5 (veryhydrophobic). For example, morphine (log P of about 0.3) is consideredhighly hydrophilic whereas NTI (log P of about 3.3) is consideredextremely hydrophobic on this Log P scale. Preferred compounds of thepresent invention have a log P value in the range of about 0.0 to about2.5.

While compounds of the present invention have shown activity in theevaluations described below, these compounds may be active in opioidreceptors by this or other mechanisms of action. Thus, the descriptionbelow of these compounds' activity in opioid receptors is not meant tolimit the present invention to a specific mechanism of action.

Six representative compounds of formula I were prepared; physical datafor these compounds is provided in Table 1.

TABLE 1 Structure and Physical Data for Selected Compounds of FormulaII. Cpd. No. R_(5–9) R₂ R₃ Formula m.p. ° C. Yield (%) 4a R₇ = tert- HCH₃ C₁₉H₂₁N₃O 118.2–118.8 91.1 butyl 5a R₇ = tert- H H C₁₈H₁₉N₃O 245–24661.9 butyl 4b R₈ = tert- H CH₃ C₂₀H₂₃N₃O₂ 119.5–120.0 73.3 butyl,R_(5 = OCH) ₃ 5b R₈ = tert- H H C₁₈H₁₉N₃O₂ 253.5–255.0 80.0 butyl, R₅ =OH 4c R₆ = tert- H CH₃ C₁₉H₂₁N₃O 175.0–175.5 71.2 butyl 5c R₆ = tert- HH C₁₈H₁₉N₃O 242.5–243.5 44.0 butyl 4d R₇ = tert- N(CH₃)₂ CH₃ C₂₁H₂₆N₄O !80% butyl 5d R₇ = tert- N(CH₃)₂ H C₂₀H₂₄N₄O ! 90% butyl 4e R₇ = tert-CH₂N(CH₃)₂ CH₃ C₂₂H₂₈N₄O ! 75% butylEvaluation of Biological Activity

A. In-vitro Binding Test:

Opioid delta human receptor: This assay measures binding of[³H]Naltrindole to human opiate δ receptors. CHO cells stablytransfected with a plasmid encoding the human opiate δ receptor are usedto prepare membranes in modified Tris-HCl pH 7.4 buffer using standardtechniques. A 0.9 microgram aliquot of membrane is incubated with 0.9 nM[³H]Naltrindole for 120 minutes at 25° C. Nonspecific binding isestimated in the presence of 10 micromolar (μM) naloxone. Membranes arefiltered and washed 3 times and the filters are counted to determine[³H]Naltrindole specifically bound. Compounds are screened at 10 μM.

Opioid kappa human receptor: This assay measures binding of[³H]Diprenorphine (DPN) to human opiate κ receptors. CHO cells stablytransfected with a plasmid encoding the human opiate κ receptor are usedto prepare membranes in modified Tris-HCl pH 7.4 buffer using standardtechniques. A 30 micrograms (μg) aliquot of membrane is incubated with0.6 nM [³H]DPN for 60 minutes at 25° C. Nonspecific binding is estimatedin the presence of 10 μM naloxone. Membranes are filtered and washed 3times and the filters are counted to determine [³H]DPN specificallybound. Compounds are screened at 10 μM.

Opioid mu human receptor: This assay measures binding of the[³H]Diprenorphine (DPN) to human opiate μ receptors. CHO-K1 cells stablytransfected with a plasmid encoding the human opiate μ receptor are usedto prepare membranes in modified Tris-HCl pH 7.4 buffer using standardtechniques. An 11 μg aliquot of membrane is incubated with 0.6 nM[³H]DPN for 2.5 hours at 25° C. Nonspecific binding is estimated in thepresence of 10 μM naloxone. Membranes are filtered and washed 3 timesand the filters are counted to determine [³H]DPN specifically bound.Compounds are screened at 10 μM.

B. In-vitro Competitive Binding:

Competitive Binding Assays. Human embryonic kidney (HEK) 293 cells (ATCCCRL, 1573) were cultured at 37° C. in Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum, 100 units/ml penicillin and100 μg/ml streptomycin sulfate. HEK293 cells were transfected byelectroporation with expression plasmids encoding murine δ or μ opioidreceptors tagged at the amino termini with the FLAG-tag epitope or thehuman κ receptor. Cells stably expressing opioid receptors were selectedin media containing 0.75 mg/ml G418 (Life Technologies, Gaithersburg,Md.).

Cell membrane preparations were collected from the stable transfectantsdescribed above. Opioid receptor binding assays were conducted induplicate on membrane preparations that had been resuspended in 50 mMTris-HCL, pH 7.5, utilizing [9-³H]bremazocine (specific activity 2.6Ci/mmol, NEN, Boston, Mass.) as radioligand and 10 μM cyclazocine todefine non-specific binding. Following a one-hour incubation on ice,binding assays were terminated by filtration through Whatman GF/Bfilters. Filters were soaked in Ecoscint liquid scintillation solution(National Diagnostics, Manville, N.J.) and filter-bound radioactivitywas measured using a Packard Tri-Carb 2100 TR liquid scintillationanalyzer. Receptor binding data were analyzed by non-linear regressionof saturation and competition curves using Prism 3.0 software (GraphPadSoftware, San Diego, Calif.). Protein concentrations were determinedwith the Bio-Rad protein microassay (Hercules, Calif.) using bovineserum albumin as standard.

Competitive Binding Assay Results. The binding affinities for compoundslisted in Table 1 (4a-c and 5a-c) were determined by competition of[9-³H]bremazocine binding to membranes prepared from stable cellsexpressing either the cloned μ, δ, or κ opioid receptors as described inthe above sections. While all compounds exhibited binding affinity foreach of the three opioid receptor subtypes (inhibition ranging from80–20%, [20 μM]), compound 5c demonstrated the greatest inhibitoryeffects. Compound 5c was non-selective among the three receptor subtypesat this high concentration and competed with [9-³H]bremazocine forbinding to the cloned μ, δ, or κ opioid receptors.

TABLE 2 Biological Data for Selected Di-substituted Triazole Compoundsof Formula II. Cpd. Receptor Affinity Selectivity No. (relative to 100%)for δ Receptor δ κ μ (δ/∞) (δ/μ) 4a 31 18 14 1.72 2.21 5a 21 48 18 0.441.17 4b 8 27 20 0.30 0.27 5b ~0 20 21 — — 4c 2 27 19 0.07 0.11 5c 39 8572 0.46 0.54

These results demonstrate that certain di-substituted triazole compoundsof the present invention are able to mimic classical opioids, forexample, in their high opioid-receptor binding affinity generally. It isalso significant that minor structural variations in the substituentscan provide substantial changes in the receptor affinity as well as theselectivity. Thus, if desired, the compounds of the present inventioncan selected based on preferred receptor affinity, receptor selectivity,pain cessation properties, or based on combinations of these and otheruseful properties. The substituted triazole compounds of the presentinvention are chemically and structurally distinct from classical opioidcompounds like morphine. Moreover, compounds of the present inventionare more easily synthesized than the classical opioids. The compounds ofthe invention can also possess improved bioavailability compared withother opioid compounds and particularly with other δ-selective opioidcompounds such as naltrindole (NTI) and spiroindanyloxymorphone (SIOM).

To determine the selectivity profile of compound 5c toward the clonedopioid receptors, competitive binding assays were performed in thepresence of increasing concentrations of compound 5c. Referring to FIG.1A-C, there is shown representative dose-response curves obtained fromcompetitive binding assays of compound 5c for the delta (δ), mu (μ), andkappa (κ) receptors, respectively. Non-linear regression analysis of thecurves yielded IC₅₀ values which were converted to inhibition constants(K_(i)) using the Cheng-Prusoff equation (K_(i)=IC₅₀/(1+C/K_(d)) where Cis the concentration, and K_(d) is the apparent dissociation constant of[9-³H]bremazocine. Apparent binding constants for compound 5c at eachreceptor subtype are listed in Table 3. These results demonstrate thatcompound 5c exhibits high binding affinity (˜100 nM) and moderateselectivity (1:3.3 μ; 1:10 κ) for the δ opioid receptor.

TABLE 3 Average observed inhibition constant (K_(i)) values forCompounds 5c and 5d. Inhibition Constant, K_(i) Compound δ μ κ 5c 136 nM  444 nM     1390 nM 5d 300 nM 4,000 nM >10,000 nM

Preliminary Test for Agonist vs. Antagonist Activity. A simple method todetermine whether a compound is acting as an agonist or antagonist at aG-Protein coupled receptor is to perform the competitive binding assayin the presence of 100 mM NaCl. The presence of NaCl in the resuspensionbuffer will result in about a 4 fold decrease in binding affinity for anopioid receptor agonist, whereas an antagonist will show about a 1 foldincrease in receptor affinity. The binding affinity curves for compound5c in the presence of NaCl shifted left in response to about a 1 foldincrease in binding affinity for all three opioid receptors. These datademonstrate that compound 5c acts as an antagonist for all of the opioidreceptors subtypes tested.

C. in-vivo test: Each compound in Table 1 was evaluated for possibleanalgesic activity in a model of radiant heat-induced tail flickresponse in mice. Male or female ICR mice provided by the animalbreeding center of MDS Pharma Services-Taiwan Ltd. were used. Spaceallocation for 10 animals was 45×23×15 cm. Mice were housed in APEC®cages (Allentown Caging, Allentown, N.J.) in a positive isolator(NuAire®, Mode: Nu-605, airflow velocity 50±5 ft/min, HEPA Filter). Allanimals were maintained in a controlled temperature (22° C.–24° C.) andhumidity (60%–80%) environment with 12 hours light-dark cycles for atleast one week in MDS Pharma Services—Taiwan Laboratory prior to beingused. Free access to standard lab chow for mice (Fuwsow Industry Co.,Limited, Taiwan) and tap water was granted. All aspects of this workincluding housing, experimentation and disposal of animals wereperformed in general accordance with the International GuidingPrinciples for Biomedical Research Involving Animals (CIOMS PublicationNo. ISBN 92 90360194, 1985). Groups of 4 male or female ICR miceweighing 22±2 gm were employed. Test substances, dissolved in a vehicleof 2% TWEEN 80/0.9% NaCl, were administrated intraperitoneally. Thecontrol group received vehicle alone. At pretreatment (0 min.) a focusedbeam of radiant heat was applied to the middle dorsal surface of thetail to elicit a “tail flick” response within about 6–7.5 seconds inpre-treated animals. Representative compounds of the present inventionthat were tested showed activity with increased response time in the“tail flick” assay compared to the response for untreated animals. Noacute toxic effects were observed.

The invention will now be illustrated by the following non-limitingExamples.

General. Chemistry. All commercial reagents and solvents were usedwithout further purification. NMR spectra were recorded on either GEQE-300 or Bruker AMX-300 spectrometers equipped with a 5.0 mmmultinuclear probe. Chemical shifts are in parts per million (ppm).Using the Bruker AMX-300 spectrometer, the proton and APT (Carbon-13)NMR spectra were acquired at 30° C. with sample spinning at 20 Hz. TheHMQC and HMBC spectra were acquired without spinning the sample. LinearPrediction and T1 noise reduction processing were applied to the F1dimensions of the HMQC and HMBC spectra. Mass spectra were determinedusing a Finnigan MAT Triple Stage (Quadrupole 7000 Mass Spectrometer(MS) equipped with and an electrospray ionization (ESI) source, and thesample was introduced into the ionization source using a HarvardApparatus 22 Syringe Pump. Organic layers obtained after extraction ofaqueous solutions were dried over anhydrous magnesium sulfate (MgSO₄)and filtered before evaporation in vacuo. Purity was determined by HPLCsystem using a Shimadzu LC-10 chromatography system equipped withLC-10AT pumps, SIL-10A XL auto injector, SCL-10A system controller,SPD-10A UV-VIS detector and Phenomenex Prodigy C18 5 micrometer (μm)particle size column, dimensions 4.6×150 mm. As the mobile phase, 60%MeOH, 40% H2O and 0.1% TFA at a flow rate of 1.0 mL/min. was used(t_(R)=retention time). Chromatograms were acquired at 245 nm and at 40°C. of column temperature. Purification yields were not optimized.Melting points were measured on a Thomas Hoover capillary melting pointapparatus and are uncorrected.

EXAMPLES Example 11-{3-[4-(tert-Butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene (4a)(Compound 4, Scheme 1, wherein R₇ is tert-butyl and R₉, R₈, R₆, and R₅are hydrogen)

To 1.86 g (0.006 M) of compound 3a in a 3-neck round bottom flask wasadded 20 mL of n-pentylformate. The resulting solution was stirred atroom temperature for 1 hour and refluxed for 3 hours. After completereaction, the product was evaporated in excess n-pentylformate underreduced pressure. The organic residue was collected by extracting withethylacetate and water three times. The organic layer was dried overanhydrous magnesium sulfate (MgSO₄) and evaporated under reducedpressure. The organic residue was purified by column chromatography(ethylacetate:hexane=1:1) and yielded the title compound 1.75 g (91.1%)HPLC: t_(R)=22.67 min. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.30 (s, 9H), 3.76(s, 3H), 6.76 (t, J=2.1 Hz, 1H), 6.81–6.85 (m, 1H), 6.99–7.03 (m, 1H),7.32–7.45 (m, 5H), 8.28 (s, 1H). ¹³C NMR (DMSO-d₆, 300 MHz): δ 31.13,34.78, 55.56, 111.68, 115.11, 118.00, 123.51, 1215.50, 128.18, 130.68,135.86, 153.07, 153.17, 160.58. MS (Infusion/ESI/MS): m/z 308 [M+H]⁺

The intermediate compound 3a was prepared as follows.

a. [4-(tert-Butyl)phenyl]-N-(3-methoxyphenyl)carboxamide (1a) (Compound1, Scheme 1, wherein R₇ is tert-butyl and R₉, R₈, R₆, and R₅ arehydrogen).

To a solution of 3 mL (0.016M) of m-anisidine dissolved in 40 mL of drytoluene was added 2.453 mL (1.1 eq) of triethylamine. The resultingsolution was stirred for 30 minutes at room temperature and 1.801 mL (1eq) of 4-tert-butylbenzoyl chloride was added slowly dropwise. Thereaction mixture was stirred for 30 minutes at room temperature andheated to about 50–60° C. for 2 hours. After complete reaction, thetriethylamine hydrochloride salt was filtered out and washed with 5 mLof dry toluene twice. The organic residue was extracted using water andtoluene twice, and the organic layer was collected. The organic layerwas dried over anhydrous magnesium sulfate (MgSO₄) and evaporated underreduced pressure. After recrystallization, the final product yield was4.06 g (89.7%). ¹³C NMR (CDCl₃, 300 MHz): δ 31.23, 35.05, 55.38, 105.83,110.50, 112.36, 125.76, 126.97, 129.76, 132.11, 139.43, 155.49, 160.27,165.85. MS (Infusion/ESI/MS): m/z 300 [M+H]⁺

b. [4-(tert-Butyl)phenyl][3-methoxyphenyl)-amino]methane-1-thione (2a)(Compound 2, Scheme 1, wherein R₇ is tert-butyl and R₉, R₈, R₆, and R₅are hydrogen).

To 4.0 g (0.014 M) of[4-(tert-butyl)phenyl]-N-(3-methoxyphenyl)carboxamide dissolved in 40 mLof dry toluene was added 1.25 g (0.2 eq) of phosphorous pentasulfide.The resulting solution was stirred for 30 minutes at room temperatureand heated to 60° C. for 4 hours. After complete reaction, the organiclayer was collected by extraction with toluene and water three times.The organic layer was dried over anhydrous MgSO₄ and evaporated underreduced pressure. After recrystallization, the final product yielded3.80 g (89.8%). ¹H NMR (DMSO-d₆, 300 MHz): δ 1.27 (s, 9H), 3.76 (s, 3H),6.84 (dd, J=1.8 Hz, J′=1.8 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.44–7.48(m, 3H), 7.62 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 11.60 (s, 1H). ¹³C NMR(DMSO-d₆, 300 MHz): δ 30.85, 34.49, 55.11, 109.37, 111.55, 115.88,124.67, 127.18, 129.13, 140.27, 141.17, 153.53, 159.12, 197.29. MS(Infusion/ESI/MS): m/z 300 [M+H]⁺

c. N³-[3-Methoxyphenyl]-p-tert-butyl-benzamidrazone (3a) (Compound 3,Scheme 1, wherein R₇ is tert-butyl and R₉, R₈, R₆, and R₅ are hydrogen).

To 5.0 g (0.017 M) of[4-(tert-butyl)phenyl][3-methoxyphenyl)-amino]methane-1-thione dissolvedin 50 mL of absolute EtOH was slowly added 5.0 mL (excess) of hydrazine.The resulting solution was stirred at room temperature for 1 hour andrefluxed for 2 hours. After complete reaction, the reaction mixture wasevaporated under reduced pressure and in vacuo to remove traces ofexcess hydrazine. The final product yielded 4.8 g (96.6%). ¹H NMR(DMSO-d₆, 300 MHz): δ 1.23 (s, 9H), 3.60 (s, 3H), 6.11 (s, 1H),6.16–6.19 (m, 1H), 6.28 (dd, J=1.8 Hz, J′=2.1 Hz, 1H), 6.99 (t, J=8.1Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H). ¹³C NMR(DMSO-d₆, 300 MHz): δ 30.85, 34.17, 54.57, 101.40, 103.91, 108.20,124.74, 125.65, 129.34, 133.13, 138.28, 144.63, 150.13, 159.87.

Example 2 1-{3-[4-(tert-Butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol(5a) (Compound 5, Scheme 1, wherein R₇ is tert-butyl and R₉, R₈, R₆, andR₅ are hydrogen)

A solution of BBr₃ in 10 mL of CH₂Cl₂ was added slowly to 1.0 g of1-{3-[4-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene (4a)dissolved in 10 mL of CH₂Cl₂. The resulting solution was stirred at roomtemperature for 2 hours. After complete reaction, the pH of the reactionmixture was adjusted to pH=2–3 using 1 M HCl solution. The organic layerwas collected by extraction with CH₂Cl₂ and water three times. Theorganic layer was dried over anhydrous magnesium sulfate (MgSO₄) andevaporated under reduced pressure. The organic residue was purified bycolumn chromatography (ethylacetate:hexane=1:1) and yielded the titlecompound 0.26 g (61.9%). HPLC:t_(R)=11.93 min. ¹H NMR (DMSO-d₆, 300MHz): δ 1.25 (s, 9H), 6.61 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 7.07 (d,J=2.1 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.42 (d,J=8.7 Hz, 2H), 8.21 (s, 1H), 10.06–10.09 (broad, 1H). ¹³C NMR (DMSO-d₆,300 MHz): δ 31.09, 34.82, 113.46, 116.53, 117.67, 122.66, 125.72,128.25, 130.69, 134.90, 153.39, 153.71, 159.15. MS (Infusion/ESI/MS):m/z 294 [M+H]⁺

Example 31-{3-[5-(tert-Butyl)-2-methoxyphenyl](1,2,4-triazol-4-yl)}-3-methoxybenzene(4b) (Compound 4, Scheme 1, wherein R₅ is methoxy, R₈ is tert-butyl andR₆, R₇, and R₉ are hydrogen)

The title compound was prepared using procedures similar to thosedescribed in Example 1 and the sub-parts thereof, except replacing the4-(tert-butyl)benzoyl chloride used in sub-part a with5-(tert-butyl)-2-methoxybenzoyl chloride 6a (Scheme 2). Compound 4b waspurified by column chromatography (ethylacetate:hexane=1:1) and yielded1.51 g (73.3%). HPLC:t_(R)=16.84 minutes. ¹H NMR (DMSO-d₆, 300 MHz): δ1.30 (s, 9H), 3.32 (s, 3H), 3.65 (s, 3H), 6.59–6.61 (m, 1H), 6.69–6.74(m, 2H), 6.73 (dd, J=3.0 Hz, J′=1.2 Hz, 1H), 7.25 (t, J=5.6 Hz, 1H),7.41 (dd, J=2.7 Hz, J′=3.0 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 8.38 (s,1H). ¹³C NMR (DMSO-d₆, 300 MHz): δ 31.42, 34.20, 54.89, 55.36, 109.54,110.77, 114.32, 115.62, 116.02, 128.67, 128.97, 130.06, 136.57, 143.86,152.05, 154.72, 160.18. MS (Infusion/ESI/MS): m/z 338.2 [M+H]⁺

The intermediate compound 6a was prepared as follows.

a. 5-(tert-Butyl)-2-hydroxybenzoic acid methyl ester (7, Scheme 2).

A solution of 10 g of methylsalicylate was added to 25 mL of PPA (2 g).The resulting solution was stirred at room temperature for 1 hr andtert-butylbromide (7.58 mL, 1 eq) was added slowly dropwise. Theresulting mixture was heated at 90° C. for 7 hr. After the reaction wascompleted, the product was purified by column chromatography usingn-hexane without extraction. The product yielded 13.13 g (96.0%). ¹H NMR(CDCl₃, 300 MHz): δ1.29 (s, 9H), 3.9 (s, 3H), 6.91 (d, J=90 Hz, 1H),7.48 (d, J=9.0 Hz, 1H), 7.82 (s, 1H), 10.62 (s, 1H).

b. 5-(tert-Butyl)-2-methoxybenzoic acid methyl ester (8, Scheme 2).

To 6.0 g of 5-(tert-butyl)-2-hydroxybenzoic acid methyl ester in a roundbottom flask was added tetrabutyl-ammoniumhydroxide 40% solution (7.45g, 1 eq). The resulting solution was stirred at room temperature for 2hr. All water was evaporated under reduced pressure and then in vacuo.To remove trace water, the salt was dried in a vacuum oven overnight andyielded 12.9 g (99%). To a solution of 12.9 g of tetra-butylammoniumsalt in 50 ml dry THF was slowly added methyliodide (3.61 mL, 2 eq). Theresulting solution was stirred at room temperature for 2 hr. After thereaction was completed, the product was filtered out using ammoniumiodide salt and washed with ethylacetate twice. The pH was adjusted topH=2–3 using 1M HCl solution. This organic layer was collected byextraction with ethylacetate and water three times. The organic layerwas dried over anhydrous magnesium sulfate (MgSO₄). The organic layerwas evaporated and the residue was purified by column chromatography(ethylacetate:hexane=1:5) (yield: 3.8 g, 60.0%) ¹H NMR (CDCl₃, 300 MHz):δ 1.30 (s, 9H), 3.86 (s, 3H), 3.90 (s, 3H), 6.90 (d, J=10.5 Hz, 1H),7.47 (d, J=9.0 Hz, 1H), 7.82 (s, 1H).

c. 5-(tert-Butyl)-2-methoxybenzoyl chloride (6a, Scheme 2).

To a solution of 3.8 g of 5-(tert-butyl)-2-methoxybenzoic acid methylester in MeOH (30 mL) was added 50% NaOH-water solution (1 mL). Theresulting solution was stirred at room temperature for 3 hr. After thereaction was complete, the pH was adjusted to pH=2–3 using 1M HCl. Thereaction mixture was collected by extraction with ethylacetate and waterthree times. The organic layer was dried over anhydrous magnesiumsulfate (MgSO₄) and evaporated under reduced pressure. Afterrecrystallization, the final product yielded 3.4 g (96%). Withoutfurther purification a solution of 3.4 g of5-(tert-butyl)-2-methoxybenzoic acid in 20 mL CH₂Cl₂ was slowly treatedwith SOCl₂ (1.2 eq). The resulting solution was stirred at roomtemperature for 2 hr. The reaction mixture was evaporated under reducedpressure and dried in a vacuum oven overnight to yield 3.4 g (91.9%).

Example 41-{3-[5-(tert-Butyl)-2-hydroxyphenyl]-(1,2,4-triazol-4-yl)}-3-phenol(5b) (Compound 5, Scheme 1, wherein R₅ is hydroxy, R₈ is tert-butyl andR₆, R₇, and R₉ are hydrogen)

Compound 5b was prepared from1-{3-[5-(tert-butyl)-2-methoxyphenyl](1,2,4-triazol-4-yl)}-3-methoxybenzene(4b) using a procedure similar to that described in Example 2. Compound5b was purified by column chromatography (ethylacetate:hexane=1:1) andyielded 0.22 g (80.0%) final product. HPLC:t_(R)=8.60 min. ¹H NMR(DMSO-d₆, 300 MHz): δ 1.00 (s, 9H), 6.83–6.86 (m, 2H), 6.97–7.00 (m,2H), 7.03–7.08 (m, 1H), 7.26 (dd, J=2.4 Hz, J′=2.4 Hz, 1H), 7.34–7.38(m, 1H), 8.22 (s, 1H), 9.40–9.70 (broad, 1H), 11.30–11.60 (broad, 1H).¹³C NMR (DMSO-d₆, 300 MHz): δ 30.77, 33.49, 109.15, 113.59, 116.77,116.87, 117.39, 123.35, 128.42, 130.71, 135.50, 140.91, 151.87, 155.37,159.06. MS (Infusion/ESI/MS): m/z 310 [M+H]⁺

Example 51-{3-[3-(tert-Butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene (4c)(Compound 4, Scheme 1, wherein R₆ is tert-butyl and R₅, R₇, R₈, and R₉are hydrogen)

The title compound was prepared using procedures similar to thosedescribed in Example 1 and the sub-parts thereof, except replacing the4-(tert-butyl)benzoyl with 3-(tert-butyl)benzoyl chloride (6b) (Scheme3). Compound 4c was purified by column chromatography(ethylacetate:hexane=1:1) and yielded 0.89 g (71.2%) final product.HPLC: t_(R)=19.79 min. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.18 (s, 9H), 3.75(s, 3H), 6.74 (t, J=2.3 Hz, 1H), 6.82–6.85 (m, 1H), 6.98–7.02 (m, 1H),7.34–7.45 (m, 5H), 8.31 (s, 1H). ¹³C NMR (DMSO-d₆, 300 MHz): δ 31.06,34.66, 55.60, 111.85, 115.06, 118.03, 125.79, 125.89, 126.00, 126.83,128.39, 130.70, 135.98, 151.40, 153.52, 160.69. MS (Infusion/ESI/MS):m/z 308 [M+H]⁺.

The intermediate compound 6b was prepared as follows.

a. 3-tert-Butyl-benzoic acid (10a, Scheme 3).

To a solution of dry toluene 53.1 mL (0.5 mole) was added anhydrousAlCl₃ (6.667 g, 0.05 mole). The resulting solution was stirred at 5° C.for 30 min while slowly treated with tert-butylchloride dropwise 5.435mL (0.05 mole) at below 10° C. The resulting solution was stirred atbelow 20° C. for 3 hr. After the reaction was complete, the organiclayer was collected by extraction with water and toluene three times.The organic layer was dried over anhydrous magnesium sulfate (MgSO₄) andevaporated under reduced pressure. This yielded a 6.44 g (87.0%) mixtureof 3-tert-butyltoluene and 4-tert-butyltoluene. Without furtherpurification of 6.44 g of the mixture was added to 20.4 g (3 eq) ofKMnO₄ solution in pyridine (96.7 mL) and water (64.5 mL). The resultingsolution was stirred at room temperature for 30 min and heated toboiling, ca.100° C. After the reaction was complete, the pH was adjustedto pH=2–3 using 1M HCl solution then the product was extracted withethylacetate and water twice. The organic layer was washed with 1M HClsolution to remove excess pyridine, then collected. The organic layerwas dried over anhydrous magnesium sulfate (MgSO₄) and evaporated underreduced pressure. Recrystallization yielded a 7.1 g (92.2%) mixture of3-tert-butyl benzoic acid and 4-tert-butylbenzoic acid. The3-tert-butylbenzoic acid and 4-tert-butylbenzoic acid were separated byrecrystallization from MeOH to provide compound 10a. HPLC t_(R)=26.63min. ¹H NMR (CDCl₃, 300 MHz): δ 1.36 (s, 9H), 7.41 (t, J=8.0 Hz, 1H),7.63–7.67 (m, 1H), 7.95 (d, J=8.0 Hz, 1H), 8.17 (s, 1H).

b. Compound 6b was prepared from 3-tert-butylbenzoic acid using aprocedure similar to that described in Example 3, sub-part c.

Example 6 1-{3-[3-(tert-Butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol(5c)

Compound 5c was prepared from1-{3-[3-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene (4c)using a procedure similar to that described in Example 2. Compound 5cwas purified by column chromatography (ethylacetate:hexane=1:1) andyielded 0.11 g (44.0%) final product. HPLC: t_(R)=10.64 min. ¹H NMR(DMSO-d₆, 300 MHz): δ 1.12 (s, 9H), 6.69 (t, J=1.5 Hz, 1H), 6.74–6.78(m, 1H) 6.87–6.91 (m, 1H) 7.27–7.43 (m, 5H), 8.77 (s, 1H). ¹³C NMR(DMSO-d₆, 300 MHz): δ 30.64, 34.16, 113.11, 116.21, 116.29, 125.01,125.26, 126.13, 126.31, 128.37, 130.41, 135.50, 150.56, 152.20, 158.80.MS (Infusion/ESI/MS): m/z 294 [M+H]⁺.

Example 71-{3-[4-(tert-butyl)phenyl]-5-N,N-dimethylamino-(1,2,4-triazol-4-yl)}-3-methoxylbenzene(4d).

To 600 mg of Compound 3 (Scheme 1) in a three-necked round bottom flaskwas added 10 ml dichloromethane and 0.74 ml triethylamine. Afterstirring at room temperature for 10 minutes, 326 mg Viehe's reagent wasadded. The suspension was stirred at reflux temperature until the soliddisappeared. After cooling to room temperature, the solution was dilutedby dichloromethane and extracted by water. The organic layer was driedby anhydrous magnesium sulfate and concentrated by evaporation undervacuum. The crude product was purified by flash chromatography to give acolorless crystal product in 80% yield. ¹H NMR(CDCL3, 400 MHz): 1.24(s,9H), 2.63(s, 6H),3.75(s, 3H), 6.95(d, J=0.9 Hz, 1H), 7.04(s, 1H),7.10(d, J=0.9 Hz, 1H), 7.25(d, J=6.7 Hz,2H), 7.32–7.34(m,2H)7.41–7.43(m, 1H), MS(EI): 351.3(M+H)⁺, 336.3, 295.3, 224.3.

Example 81-{3-[4-(tert-butyl)phenyl]-5-N,N-dimethylamino-(1,2,4-triazol-4-yl)}-3-phenol(5d)

Compound 4d (17.5 mg) was dissolved in 5 ml dry dichloromethane, andcool the solution to −78° C. 0.17 ml 1M Boron tribromide solution wasdropped carefully under stirring. After dropping, the solution wasstirred at room temperature for 3 hours. The solution was transferred tobeaker and neutralized by hydrogen chloride solution. The organicsolution was extracted by water for two times and dried by anhydrousmagnesium sulfate. After concentration the crude product was purified byflash chromatography to get a white solid with 90% yield. ¹H NMR(CDCL3,400 MHz): 1.23(s, 9H), 2.61(s, 6H), 6.64(d, J=7.9 Hz, 1H), 6.99(s, 1H),7.10(d, J=8.3 Hz, 1H), 7.22–7.27(m, 5H), 10.93(s, 1H). MS(EI):337.4(M+H)⁺, 322.3, 307.3, 281.3, 266.3, 210.3.

Example 91-{3-[4-(tert-butyl)phenyl]-5-N,N-dimethylaminoethyl-(1,2,4-triazol-4-yl)}-3-methoxylbenzene(4e)

Compound 3 (Scheme 1, 123 mg, 0.4 mmol) was dissolved in 5 ml dry DMF atthe room temperature. Eschenmoser's reagent 183 mg (1 mmol) was addedrapidly under argon. The suspension was stirred at the 80° C. for 5hours. After cooling to room temperature the solution was concentratedunder vacuum and the residue was dissolved in acetone. The product wasfurther purified by flash chromatography to give colorless syrup productwith yield of 75%. ¹H NMR (CDCL3, 400 MHz): 1.27(s, 9H), 2.27(s, 6H),3.43(s, 2H), 3.78(s, 3H), 6.85(d, J=7.9 Hz, 1H), 6.97(s, 1H), 7.01(D,J=8.2 Hz, 1H), 7.28–7.40(m, 5H). MS (EI): 365.2(M+H)⁺, 320.2, 308.2.

Example 10

The following illustrate representative pharmaceutical dosage forms,containing a compound of the invention (‘Compound X’), such as acompound of formula I or II for therapeutic or prophylactic use inhumans.

(i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet ‘Compound X’ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodiumhydroxide solution q.s. (pH adjustment to 7.0–7.5) Water for injectionq.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml ‘Compound X’ (free acidform) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1Polyethylene glycol 400 200.0 01 N Sodium hydroxide solution q.s. (pHadjustment to 7.0–7.5) Water for injection q.s. ad 1 mL (vi) Aerosolmg/can ‘Compound X’ 20.0 Oleic acid 10.0 Trichloromonofluoromethane5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula I:

wherein: R₁ is aryl, Het, (C₁₋₇)alkyl, or (C₃₋₁₂)cycloalkyl, which(C₁₋₇)alkyl or (C₃₋₁₂)cycloalkyl are each independently optionallysubstituted with from 1 to 5 aryl, Het, OR_(a), halo, NO₂, NR_(a)R_(b),cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a), S(O)_(m)NR_(a)R_(b), orP(═O)(OR_(a))(R_(a)); R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, aryl,Het, or a group that includes one or more basic atoms; R₃ is H, or(C₁₋₇)alkyl; each R₄ is independently OR_(a), trifluoromethoxy,trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a),SO_(m)R_(a), S(O)_(m)NR_(a)R_(m), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl,(C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl; R_(a) and R_(b)are each independently H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,(C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl, or R_(a) and R_(b) togetherwith a nitrogen to which they are attached form a Het; wherein any arylor Het of R¹ or R² is optionally substituted with from 1 to 4substituents independently selected from OR_(a), trifluoromethoxy,trifluoromethyl, halo, NO₂, NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a),SO_(m)R_(a), S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl,(C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl; and m is 0, 1,or 2; n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein R₂ is H; (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, or Het; R_(c) andR_(d) are each independently H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,(C₂₋₇)alkanoyl, (C₂₋₇)alkanoyloxy, or aryl; and n is 0 or
 1. 3. Thecompound of claim 1 wherein R₁ is aryl.
 4. The compound of claim 1wherein R₁ is aryl substituted with from 1 to 5 substituents.
 5. Thecompound of claim 1 wherein R₁ is phenyl substituted with from 1 to 5substituents.
 6. The compound of claim 1 wherein R₁ is phenylsubstituted with from 1 to 3 substituents.
 7. The compound of claim 1wherein R₁ is phenyl substituted with one n-butyl, iso-butyl, methyl,ethyl, or tert-butyl.
 8. The compound of claim 1 wherein R₁ is phenylsubstituted with one tert-butyl.
 9. The compound of claim 1 wherein R₁is 2-tert-butylphenyl, 3-tert-butylphenyl, or 4-tert-butylphenyl. 10.The compound of claim 1 wherein R₁ is 3-tert-butylphenyl, or4-tert-butylphenyl.
 11. The compound of claim 1 wherein R₁ is phenylsubstituted with a (C₁₋₇)alkyl and a (C₁₋₇)alkoxy.
 12. The compound ofclaim 1 wherein R₁ is phenyl substituted with a tert-butyl, and amethoxy.
 13. The compound of claim 1 wherein R₁ is Het.
 14. The compoundof claim 1 wherein R₁ is Het substituted with from 1 to 4 substituents.15. The compound of claim 1 wherein R₂ is H.
 16. The compound of claim 1wherein R₂ is NR_(a)R_(b).
 17. The compound of claim 1 wherein R₂ isOR_(a).
 18. The compound of claim 1 wherein R₂ is SR_(a).
 19. Thecompound of claim 1 wherein R₂ is (C₁₋₇)alkyl or (C₃₋₁₂)cycloalkyl. 20.The compound of claim 1 wherein R₂ is NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.21. The compound of claim 1 wherein R₂ is morpholino, or thiomorpholinoring.
 22. The compound of claim 1 wherein R₂ is H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, or Het.
 23. Thecompound of claim 1 wherein R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, Het, R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycoalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂ CH₂O)_(p), orR_(x)—(CH₂ CH₂S)_(p); wherein R_(x) is OR_(a), SR_(a), NR_(c)R_(d),piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino; andp is 1–7.
 24. The compound of claim 1 wherein R₂ is H, (C₁₋₇)alkyl,(C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, Het,R_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycoalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) isNR_(c)R_(d); and p is 1–7.
 25. The compound of claim 1 wherein R₂ is H,(C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(a)R_(d), aryl, Het,R_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) ispiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino; andp is 1–7.
 26. The compound of claim 1 wherein R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂CH₂O)_(p), orR_(x)—(CH₂CH₂S)_(p); wherein R_(x) is group that includes one or morebasic atoms; and p is 1–7.
 27. The compound of claim 1 wherein R₂ isR_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) is OR_(a),SR_(a), NR_(c)R_(d), piperazino, pyrrolidino, piperidino, morpholino, orthiomorpholino; and p is 1–7.
 28. The compound of claim 1 wherein R₂ isR_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) isNR_(c)R_(d); and p is 1–7.
 29. The compound of claim 1 wherein R₃ is H.30. The compound of claim 1 wherein R₃ is (C₁₋₇)alkyl.
 31. The compoundof claim 1 wherein R₃ is methyl.
 32. The compound of claim 1 wherein R₃is ethyl.
 33. The compound of claim 1 wherein R₃ is tert-butyl.
 34. Thecompound of claim 1 wherein n is
 0. 35. The compound of claim 1 whereinn is
 1. 36. The compound of claim 1 which is a compound of formula II:

wherein: R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, aryl, Het, or a groupthat includes one or more basic atoms; R₃ is H, or (C₁₋₇)alkyl; each R₄is independently OR_(a), trifluoromethoxy, trifluoromethyl, halo, NO₂,NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₁₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl; R₅, R₆, R₇, R₈ and R₉ are eachindependently H, OR_(a), trifluoromethoxy, trifluoromethyl, halo, NO₂,NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₂₋₇)cycloalkyl; R_(a) and R_(b) are eachindependently H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or aryl, or R_(a) and R_(b) together with a nitrogento which they are attached form a Het; wherein any aryl or Het of R² isoptionally substituted with from 1 to 4 substituents independentlyselected from OR_(a), trifluoromethoxy, trifluoromethyl, halo, NO₂,NR_(a)R_(b), cyano, CONR_(a)R_(b), CO₂R_(a), SO_(m)R_(a),S(O)_(m)NR_(a)R_(b), P(═O)(OR_(a))(R_(a)), (C₁₋₇)alkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or (C₃₋₁₂)cycloalkyl; and m is 0, 1, or 2; and n is0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
 37. Thecompound of claim 36 wherein R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl,OR_(a), SR_(a), NR_(c)R_(d), aryl, or Het; R_(c) and R_(d) are eachindependently H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, (C₂₋₇)alkanoyl,(C₂₋₇)alkanoyloxy, or aryl; and n is 0 or
 1. 38. The compound of claim36 wherein R₂ is H.
 39. The compound of claim 36 wherein R₂ isNR_(a)R_(b).
 40. The compound of claim 36 wherein R₂ is OR_(a).
 41. Thecompound of claim 36 wherein R₂ is SR_(a).
 42. The compound of claim 36wherein R₂ is (C₁₋₇)alkyl or (C₃₋₁₂)cycloalkyl.
 43. The compound ofclaim 36 wherein R₂ is a piperazino, pyrrolidino, piperidino,morpholino, or thiomorpholino ring.
 44. The compound of claim 36 whereinR₂ is morpholino, or thiomorpholino ring.
 45. The compound of claim 36wherein R₂ is H, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a),NR_(c)R_(d), aryl, or Het.
 46. The compound of claim 36 wherein R₂ is H,(C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, Het,R_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) is OR_(a),SR_(a), NR_(c)R_(d), piperazino, pyrrolidino, piperidino, morpholino, orthiomorpholino; and p is 1–7.
 47. The compound of claim 36 wherein R₂ isH, (C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl,Het, R_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂ CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) isNR_(c)R_(d); and p is 1–7.
 48. The compound of claim 36 wherein R₂ is H,(C₁₋₇)alkyl, (C₃₋₁₂)cycloalkyl, OR_(a), SR_(a), NR_(c)R_(d), aryl, Het,R_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂ CH₂O)_(p); or R_(x)—(CH₂S)_(p); wherein R_(x) is piperazino,pyrrolidino, piperidino, morpholino, or thiomorpholino; and p is 1–7.49. The compound of claim 36 wherein R₂ is R_(x)—(C₁₋₇)alkyl,R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy, R_(x)—(CH₂CH₂O)_(p), orR_(x)—(CH₂CH₂S)_(p); wherein R_(x) is group that includes one or morebasic atoms; and p is 1–7.
 50. The compound of claim 36 wherein R₂ isR_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) is OR_(a),SR_(a), NR_(a)R_(d), piperazino, pyrrolidino, piperidino, morpholino, orthiomorpholino; and p is 1–7.
 51. The compound of claim 36 wherein R₂ isR_(x)—(C₁₋₇)alkyl, R_(x)—(C₃₋₁₂)cycloalkyl, R_(x)—(C₂₋₇)alkoxy,R_(x)—(CH₂CH₂O)_(p), or R_(x)—(CH₂CH₂S)_(p); wherein R_(x) isNR_(c)R_(d); and p is 1–7.
 52. The compound of claim 1 wherein R₂ isR_(x)—(C₁₋₇)alkyl or NR_(c)R_(d), wherein R_(x) is NR_(c)R_(d); and R₃is H.
 53. The compound of claim 36 wherein R₃ is H.
 54. The compound ofclaim 36 wherein R₃ is (C₁₋₇)alkyl.
 55. The compound of claim 36 whereinR₃ is methyl.
 56. The compound of claim 36 wherein R₃ is ethyl.
 57. Thecompound of claim 36 wherein R₃ is tert-butyl.
 58. The compound of claim36 wherein n is
 0. 59. The compound of claim 36 wherein n is
 1. 60. Thecompound of claim 36 wherein R₅, R₆, R₇, R₈, or R₉ is (C₁₋₇)alkyl or(C₃₋₁₂)cycloalkyl.
 61. The compound of claim 36 wherein R₅, R₆, R₇, R₈,or R₉ is (C₁₋₇)alkoxy.
 62. The compound of claim 36 wherein R₅, R₆, R₇,R₈, or R₉ is OCH₃.
 63. The compound of claim 36 wherein R₅, R₆, R₇, R₈,or R₉ is tert-butyl.
 64. The compound of claim 36 wherein R₅ istert-butyl.
 65. The compound of claim 36 wherein R₆ is tert-butyl. 66.The compound of claim 36 wherein R₇ is tert-butyl.
 67. The compound ofclaim 36 wherein R₅, R₆, R₇, R₈, or R₉ is OH.
 68. The compound of claim36 wherein R₅, R₆, R₇, R₈, and R₉ are H.
 69. The compound of claim 36wherein R₅, R₆, R₇, R₈, or R₉ is halo.
 70. The compound of claim 36wherein R₅, R₆, R₇, R₈, or R₉ is NO₂, NH₂, (C₂₋₇)alkanoyloxy, or(C₃₋₁₂)cycloalkyl.
 71. The compound of claim 36 wherein R₅ is OCH₃ andR₈ or R₉ is tert-butyl.
 72. The compound of claim 36 wherein R₅ is OHand R₈ or R₉ is tert-butyl.
 73. The compound of claim 36 wherein R₅ orR₆ is OCH₃, and R₇, R₈, or R₉ is tert-butyl.
 74. The compound of claim36 wherein R₅ or R₆ is OH, and R₇, R₈, or R₉ is tert-butyl.
 75. Thecompound of claim 1 which is1-{3-[4-(tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-methoxybenzene;1-{3-[4-tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol;1-{3-[5-(tert-butyl)-2-methoxyphenyl](1,2,4-triazol-4-yl)}-3-methoxybenzene;1-{3-[5-(tert-butyl)-2-hydroxyphenyl]-(1,2,4-triazol-4-yl)}-3-phenol;1-{3-[3-tert-butyl)phenyl]-(1,2,4-triazol-4-yl-)}-3-methoxybenzene;1-{3-[3-(tert-butyl)phenyl-(1,2,4-triazol-4-yl)}-3-phenol; or1-{5-(tert-butyl)-2-methoxyphenyl](1,2,4-triazol-4-yl)}-3-phenol; or apharmaceutically acceptable salt thereof.
 76. The compound of claim 1which is 1-{3-[3-tert-butyl)phenyl]-(1,2,4-triazol-4-yl)}-3-phenol; or apharmaceutically acceptable salt thereof.
 77. A pharmaceuticalcomposition comprising a compound of claim 1 in combination with apharmaceutically acceptable diluent or carrier.
 78. A therapeutic methodfor treating pain in a mammal comprising administering an effectiveamount of a compound of claim 1 to the mammal.
 79. The compound of claim1 which is1-{3-[4-(tert-butyl)phenyl]-5-N,N-dimethylamino-(1,2,4-triazol-4-yl)}-3-methoxylbenzene;1-{3-[4-tert-butyl)phenyl]-5-N,N-dimethylamino-(1,2,4-triazol-4-yl)}-3-phenol;or1-{3-[4-tert-butyl)phenyl]-5-N,N-dimethylaminoethyl-(1,2,4-triazol-4-yl)}-3-methoxylbenzene;or a pharmaceutically acceptable salt thereof.